2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport

Bioorg Med Chem Lett. 2016 Feb 1;26(3):1044-1047. doi: 10.1016/j.bmcl.2015.12.031. Epub 2015 Dec 11.

Abstract

Herein, we report the discovery of 2-amino-4-bis(aryloxybenzyl)aminobutanoic acids as novel inhibitors of ASCT2(SLC1A5)-mediated glutamine accumulation in mammalian cells. Focused library development led to two novel ASCT2 inhibitors that exhibit significantly improved potency compared with prior art in C6 (rat) and HEK293 (human) cells. The potency of leads reported here represents a 40-fold improvement over our most potent, previously reported inhibitor and represents, to our knowledge, the most potent pharmacological inhibitors of ASCT2-mediated glutamine accumulation in live cells. These and other compounds in this novel series exhibit tractable chemical properties for further development as potential therapeutic leads.

Keywords: ASCT2; Cancer; Glutamine; Metabolism; SLC1A5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / antagonists & inhibitors
  • Amino Acid Transport System ASC / metabolism*
  • Animals
  • Binding Sites
  • Butyrates / chemistry*
  • Butyrates / metabolism
  • Cell Line
  • Glutamine / metabolism*
  • HEK293 Cells
  • Humans
  • Minor Histocompatibility Antigens
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Rats
  • Structure-Activity Relationship

Substances

  • Amino Acid Transport System ASC
  • Butyrates
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human
  • Glutamine